More than 400,000 people living in the US have Down syndrome, a congenital disorder arising from the presence of three, rather than two, copies of chromosome 21. With a life expectancy of 60 years, individuals with Down syndrome are in need of health care that is preventative, evidence-based, and addresses the needs unique to Down syndrome. Increased risks of obesity and thyroid disease have been ascribed to Down syndrome, but the relevance of these issues to cardiovascular and metabolic (cardiometabolic) risk, body image, and quality of life, and their management have not been fully explored. In fact, individuals with Down syndrome have long been considered protected from cardiovascular disease. Unfortunately, the medical community may have been lulled into a false sense of security as more recent evidence suggests that individuals with Down syndrome are actually at increased risk for cardiovascular disease. Because many adult diseases have origins in childhood, examining risks and potential interventions in childhood and adolescence is the key to prevention. Moreover, adolescents with Down syndrome, like others with intellectual disabilities, may have physical, medical, and developmental issues that challenge traditional treatment paradigms and compromise quality of life and body image. The overall objective of this project is to provide a better understanding of the impact of obesity and thyroid dysfunction and their treatments on long-term cardiometabolic risk in adolescents with Down syndrome. This study also hopes to broaden the understanding of quality of life, body image and lifestyle (physical activity and dietary patterns) in these adolescents. Aims: 1) To compare the relationship between body mass index and adiposity (measured by DXA), and cardiometabolic risk factors (non-HDL cholesterol, lipoprotein subclass particles, blood pressure, insulin resistance, glucose tolerance, inflammatory markers, and adipokines) and arterial stiffness (a marker of cardiovascular end organ injury) in pre-adolescents and adolescents with Down syndrome, and in age-, sex-, race-, ethnicity- and BMI-Z score- matched controls. 2) To determine the effect of thyroxine replacement on body mass index, fat mass, cardiometabolic risk factors, and quality of life (QOL) in pre-adolescents and adolescents with Down syndrome and subclinical hypothyroidism. Secondary Aim) To examine the relationship between obesity, lifestyle (physical activity, nutrition), body image, and quality of life in DS, and to explore bariers to maintaining a healthy weight in children with DS.. These studies strive to improve the health care of children and adults with Down syndrome by providing scientific evidence on which to base cardiovascular and metabolic screening and management guidelines. PUBLIC HEALTH RELEVANCE: Individuals with intellectual and developmental disabilities are at particular risk for co-morbidities that compromise health and quality of life, but evidence to direct their management is frequently lacking. This study will provide important information to inform the clinical management of obesity, cardiometabolic risk, and thyroid dysfunction in adolescents with Down syndrome. This evidence may provide the foundation to advance prevention and treatment strategies for this underserved group with intellectual and developmental disabilities at high-risk for obesity and its life-long consequences.